Abstract This is a new application designed to study the novel roles of intestinal NHE8 on mucosal hemostasis. We have made major discoveries in this field, being the first lab to clone and characterize its expression and transport kinetics in 2005. We have described changes in postnatal expression of NHE8, defined its regulation by growth factor and hormones, and (of importance for this proposal) described its abundant expression in the goblet cells and colonic crypts. We developed NHE8-deficient mice (NHE8KO) and demonstrated fascinating phenotypes ranging from the impaired gut mucosal integrity (defects in goblet and Paneth cells, enhanced susceptibility to mucosal injury, microbial dysbiosis, increased bacterial adhesion and disruption of the mucus layer), to male infertility and development of dry eye syndrome. These and additional preliminary observations presented in this proposal led us to hypothesize that this transporter plays pleiotropic roles in mucosal homeostasis and that its reduced expression in IBD contributes to intestinal inflammation and susceptibility to colorectal cancer. To test this hypothesis, we formulated the following Aims: Aim 1: Determine the mechanism of NHE8 involvement in goblet cell function Aim 2: Characterize NHE8 expression in human UC patients and the microbial and inflammatory consequences of its loss Aim 3: Determine the roles of NHE8 in tumorigenesis We expect that the planned studies will be transformative and lead to the creation of a new paradigm regard- ing the role of epithelial Na+/H+ exchange, NHE8 in particular, in gut health.